Signaling mechanisms at synapses requires a precise number and arrangement of receptors, ion channels, and adhesion molecules. AMPA-type ionotropic glutamate receptors are the major mediators of fast excitatory synaptic transmission in the brain, and alterations in the number of AMPA receptors at the synapse is a critical feature of synapse formation, maturation, and synaptic plasticity. Although previous studies have helped define the functional significance of AMPA receptor trafficking during NMDA receptor-dependent synaptic potentiation at diverse glutamatergic synapses, the protein machinery that transports AMPA receptors through intracellular compartments and the mechanisms by which this machinery senses NMDA receptor- dependent Ca2+ influx remain poorly understood. To address these important questions, my laboratory has initiated a program of cell biological and physiological studies to analyze the intracellular signaling pathways that activate endosomal transport of AMPA receptors in dendrites and dendritic spines - the primary postsynaptic compartment in the mammalian brain. We have identified a key actin-based motor protein, myosin Vb (MyoVb), which resides in dendritic spines, traffics AMPA receptors, and responds to elevated intracellular Ca2+ by associating with AMPA receptor- containing recycling endosomes (REs) through the Rab11/Rab11-FIP2 endosomal adaptor complex. Further, we have recently found that activation of MyoVb by NMDA receptor-induced Ca2+ influx leads to the physical translocation of REs into dendritic spines and subsequent local spine exocytosis of AMPA receptors and other membrane material for synaptic potentiation and spine growth during long-term potentiation (LTP). Taking advantage of these preliminary data and our ability to monitor and manipulate endosomal transport in dendrites and spines, we propose to define the underlying molecular and cellular mechanisms that activate, regulate, and terminate AMPA receptor transport by the MyoVb/Rab11/Rab11-FIP2 complex. This work will provide insight into fundamental mechanisms that underlie neuronal signaling and synaptic plasticity. Moreover, because endosomal sorting and transport of AMPA receptors regulates plasticity in diverse neural circuits in a wide range of pathologic insults and in response to therapeutic agents relevant to numerous neurologic and psychiatric diseases, these studies hold promise for the development of novel therapeutic strategies. PUBLIC HEALTH RELEVANCE: The proposed research will uncover molecular mechanisms that regulate brain cell communication at synapses. Abnormal function of synapses contributes to epilepsy, memory decline, depression, autism, schizophrenia, and addiction. By helping to understand how nerve cell synapses are adjusted during brain development and modified as we learn, the proposed research will define novel targets and therapeutic strategies for these devastating neurological and psychiatric disorders, which currently have a profound negative impact on public health.